Contrast agents may be administered in medical imaging procedures, for example X-ray, magnetic resonance and ultrasound imaging, to enhance the image contrast in images of a subject, generally a human or non-human animal body. The resulting enhanced contrast enables different organs, tissue types or body compartments to be more clearly observed or identified. In X-ray imaging the contrast agents function by modifying the X-ray absorption characteristics of the body sites in which they distribute; magnetic resonance contrast agents generally function by modifying the characteristic relaxation times T.sub.1 and T.sub.2 of the nuclei, generally water protons, from the resonance signals of which the images are generated; and ultrasound contrast agents function by modifying the speed of sound or the density in the body sites into which they distribute.
The X-ray contrast agents first developed, barium sulfate and sodium iodide, have been superseded by iodinated organic compounds, in particular triiodophenyl compounds. Improvements in systemic toxicity over the last 40 years have also been achieved by the development of non-ionic iodinated X-ray contrast agents (see Shaw in "Radiopaques", CRC Handbook of Vitamins, Hormone and Radiopaques, CRC Press, p. 229-243). More recent improvements have come from the development of the so-called dimer X-ray contrast agents, compounds containing two triiodophenyl moieties per molecule (see McClennan in Introduction to Supplement in Investigative Radiology, 19; S289-S292 (1984)).
As the X-ray absorption cross-sections of the elements generally increase with increasing atomic number and as such cross-sections are dependent on the wavelength of the X-rays there has been some desire to utilize the X-ray absorption properties of the lanthanides and other high atomic number metals to develop contrast agents with improved X-ray attenuation especially at the wavelengths used in CT; however these attempts have generally been relatively unsuccessful.
Thus, for example, Nalbandian et al. (see Ann. N.Y. Acad. Sci. 78: 779 (1959)) and Shapiro et al. (see Ann. N.Y. Acad. Sci. 78: 756 (1959)) proposed the use of the diethylenetetraaminepentaacetic acid (DTPA) chelate of bismuth (BiDTPA) and the ethylenediaminetetraacetic acid (EDTA) chelate of lead (PbEDTA) as radiographic contrast agents but encountered problems of solubility and toxicity. In U.S. Pat. No. A-4,176,173 Winchell et al. described the use of simple hafnium or tantalum complexes as X-ray contrast agents and more recently, ytterbium DTPA has been studied as an intravascular X-ray contrast agent, and an LD.sub.50 of 10 mmoles/kg has been reported (see Unger et al. Invest. Radiol. 21:802 (1986)).
In MRI, the use of paramagnetic metal ions, such as Mn(II), as contrast agents was first proposed by Lauterbur et al. in 1978 (see pages 752-759 in "Electrons to Tissues--Frontiers of Biological Energetics" Vol. 1, edited by Dutton et al., Academic Press, N.Y., 1978) and more recently Schering AG in U.S. Pat. No. A-4,647,447 proposed the use of salts of gadolinium(III) chelates of DTPA.
In order to achieve tissue-specific MRI contrast enhancement or to enhance relaxivity the coupling of paramagnetic chelates, such as GdDTPA, or metal complexing groups to macromolecular carriers or biomolecules, such as polysaccharides, proteins, antibodies, liposomes, enzymes, polyethyleneimines etc. has been proposed by several researchers--see for example EP-A-130934 (Schering), EP-A-136812 (Technicare), EP-A-184899 (Nycomed), EP-A-186947 (Nycomed) , EP-A-277088 (Schering), EP-A-305320 (Schering), WO-A-88/07521 (Schering), WO-A-88/08422 (Schering), WO-A5/05554 (Amersham) , WO-A-89/06979 (Nycomed) , EP-A-331616 (Schering) and Schmiedl et al. Radiology 162:205 (1987). Furthermore, WO-A-88/01178 (Dow) discloses attempts made to chelate metal ions with carboxylate-terminal "starburst dendrimers" and to conjugate antibodies to such dendrimers, however the therapeutic or diagnostic utility of such structures has not been established.
The visualization of certain disease states such as cancer can benefit particularly from the use of tissue targeting contrast agents. Thus for example, in MRI it may be necessary to deliver 100-1000 paramagnetic centres to a tumour to obtain sufficient relaxation enhancement for visualization. Macromolecular polychelates for use in this regard have been proposed but attempts to prepare such macromolecular polychelates and then to attach them to target-specific proteins such as antibodies have not met with great success (see for example Manabe et al. in Biochimica et Biophysica Acta 883:460 (1986) and Schreve et al. in Magnetic Resonance in Medicine 3: 336 (1986)).
Thus, a need still remains for alternative contrast agents with reduced toxicity, enhanced contrast characteristics and/or modified biological properties and, more especially in the field of X-ray contrast agents, significant opportunity exists for improvement in the reduction of contrast media cost and toxicity, in the reduction of patient discomfort and in the reduction of the incidence of side reactions, enzymatic deiodination, etc.
The disclosures of each of the publications and other documents referred to above, as well as each of those referred to hereinafter, are incorporated by reference in the present specification.